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  • Title: Modulating the selectivity of matriptase-2 inhibitors with unnatural amino acids.
    Author: St-Georges C, Désilets A, Béliveau F, Ghinet M, Dion SP, Colombo É, Boudreault PL, Najmanovich RJ, Leduc R, Marsault É.
    Journal: Eur J Med Chem; 2017 Mar 31; 129():110-123. PubMed ID: 28219045.
    Abstract:
    Matriptase-2, a type II transmembrane serine protease (TTSP), is expressed in the liver and regulates iron homeostasis via the cleavage of hemojuvelin. Matriptase-2 emerges as an attractive target for the treatment of conditions associated with iron overload, such as hemochromatosis or beta-thalassemia. Starting from the crystal structure of its closest homolog matriptase, we constructed a homology model of matriptase-2 in order to further optimize the selectivity of serine trap peptidomimetic inhibitors for matriptase-2 vs matriptase. Careful modifications of the P4, P3 and P2 positions with the help of unnatural amino acids led to a thorough understanding of Structure-Activity Relationship and a >60-fold increase in selectivity for matriptase-2 vs matriptase. Additionally, the introduction of unnatural amino acids led to significant increases in plasma stability. Such compounds represent useful pharmacological tools to test matriptase-2 inhibition in a context of iron overload.
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